Pain - particularly chronic pain - is a major cause of morbidity, especially in patients with cancer or neuropathic pain. These conditions are often refractory to treatment. The purpose of this research is to develop particulate prolonged duration local anesthetics (PDLA) employing site 1 sodium channel blockers such as saxitoxin (STX). To date, this line of inquiry has been very productive; since the current R01 began 3.5 years ago, we have produced 31 papers, and met or exceeded the goals of our Specific Aims. The underlying hypothesis - which was validated in the preceding research - is that STX, encapsulated in combination with compounds such as conventional local anesthetics and steroids, can produce extremely long nerve blocks. As envisioned here, PDLA could last weeks to months for chronic pain, or could be tailored to shorter durations for other (e.g. perioperative) applications. Our research could potentially be applicable to any excitable tissue, and in fact to any environment where controlled release could be useful. One specific aim of this research is to resolve difficult formulation problems such as burst release, which arise in encapsulating potentially toxic hydrophilic molecules. Our base formulation is a liposome containing saxitoxin and other drugs, where we have shown we can obtain nerve blocks lasting a week with minimal systemic and local toxicity. We propose a spectrum of potential modifications to produce yet longer blocks while maintaining safety. These include producing single-agent microparticles, constructing secondary polymeric shells, use of hydrogels inside or outside of the particles, and devising macroscopic devices. An equally important aim will be the in vivo assessment of the efficacy and toxicity of these new formulations by neurobehavioral tests in rats and rabbits, and by following serum drug levels. Another crucial aspect of the research, which has not received sufficient attention, will be to study the development of inflammation, myotoxicity, and neurotoxicity with these formulations, and means of preventing them.